Cancer Res Treat.  2023 Jul;55(3):814-831. 10.4143/crt.2022.1315.

Genomic Characteristics and the Potential Clinical Implications in Oligometastatic Non–Small Cell Lung Cancer

• Liao R
• Chen K
• Li J
• He H
• Yi G
• Huang M
• Chen R
• Shen L
• Zhang X
• Xu Z
• Yang Z
• Peng Y

• KMID: 2544163
• DOI: http://doi.org/10.4143/crt.2022.1315

Abstract

Purpose
Oligometastatic non–small cell lung cancer (NSCLC) patients have been increasingly regarded as a distinct group that could benefit from local treatment to achieve a better clinical outcome. However, current definitions of oligometastasis are solely numerical, which are imprecise because of ignoring the biological heterogeneity caused by genomic characteristics. Our study aimed to profile the molecular alterations of oligometastatic NSCLC and elucidate its potential difference from polymetastasis.
Materials and Methods
We performed next-generation sequencing to analyze tumors and paired peripheral blood from 77 oligometastatic and 21 polymetastatic NSCLC patients to reveal their genomic characteristics and assess the genetic heterogeneity.
Results
We found ERBB2, ALK, MLL4, PIK3CB, and TOP2A were mutated at a significantly lower frequency in oligometastasis compared with polymetastasis. EGFR and KEAP1 alterations were mutually exclusive in oligometastatic group. More importantly, oligometastasis has a unique significant enrichment of apoptosis signaling pathway. In contrast to polymetastasis, a highly enriched COSMIC signature 4 and a special mutational process, COSMIC signature 14, were observed in the oligometastatic cohort. According to OncoKB database, 74.03% of oligometastatic NSCLC patients harbored at least one actionable alteration. The median tumor mutation burden of oligometastasis was 5.00 mutations/Mb, which was significantly associated with smoking, DNA damage repair genes, TP53 mutation, SMARCA4 mutation, LRP1B mutation, ABL1 mutation.
Conclusion
Our results shall help redefine oligometastasis beyond simple lesion enumeration that will ultimately improve the selection of patients with real oligometastatic state and optimize personalized cancer therapy for oligometastatic NSCLC.

Keyword

Non-small cell lung cancer; Oligometastatic; Genomic profiling; High-throughput nucleotide sequencing; Tumor mutational burden

Figure

• 

  Fig. 1 Alteration landscape of 77 oligometastatic (A) and 21 polymetastatic (B) non–small cell lung cancer (NSCLC) patients. The heat map shows top 20 genes across all samples, with genes ranked by mutation frequency. Top bar summarizes the total number of mutations in each patient (columns). Side bar (rows) summarizes the percentage of tumors with mutation in each gene and mutation composition for each gene in the entire cohort. Bottom heat map, group, smoking, sex, and age. Different colors denote different types of mutations and different clinical features. Single nucleotide variations (C), Ti/Tv ratios in oligometastasis (D) and polymetastasis (E), respectively. Differentially mutated genes between oligometastatic and polymetastatic NSCLC (F). The mutual exclusivity and co-occurrence analysis in each group (G, H).

• 

  Fig. 2 Top 15 enriched pathways by Kyoto Encyclopedia of Genes and Genomes (KEGG) (A) and functional terms by GO enrichment (B) of somatic mutations in oligometastatic and polymetastatic non–small cell lung cancer (NSCLC) patients. Count: the number of mutations enriched in this signaling pathway or functional term. GO, gene ontology; HIF-1, hypoxia inducible factor 1; KEGG, Kyoto Encyclopedia of Genes and Genomes; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; NSCLC, non–small cell lung cancer; PI3K, phosphoinositide 3-kinase; VEGF, vascular endothelial growth factor.

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  Fig. 3 Mutational signatures in oligometastatic and polymetastatic non–small cell lung cancer (NSCLC) patients. (A) Ninety-six subtype classification of the mutational signature of oligometastatic and polymetastatic NSCLC. (B) Histogram of mutation signatures for oligometastatic and polymetastatic NSCLC patients. RSS, residual sum of squares.

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  Fig. 4 Somatic alterations identified by the 1021-panel that are clinically actionable in oligometastatic group. (A) Samples were classified according to their highest level of actionable alterations. (B) Distribution of alteration types. (C) Distribution of levels of actionable alterations. ALK, anaplastic lymphoma kinase; BRAF, B-Raf proto-oncogene, serine/threonine kinase; CDKN2A, cyclin dependent kinase inhibitor 2A; EGFR, epidermal growth factor receptor; ERBB2, Erb-B2 receptor tyrosine kinase 2; PTEN, phosphatase and tensin homolog.

• 

  Fig. 5 (A) Distribution of tumor mutation burden (TMB) in 42 oligometastatic and nine polymetastatic non–small cell lung cancer patients. Non-parametric test of TMB according to metastatic state (B), smoking status (C), DNA damage repair (DDR) genes (D), TP53 genotype (E), SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4 (SMARCA4) genotype (F), LDL receptor related protein 1B (LRP1B) genotype (G), and ABL1 genotype (H).

Reference

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